Drugs acting on Immune System

Question 1

The immune system?

Answer 1

●The immune system is a system of defense against foreign bodies.
》It can differentiate its own cells from cells with foreign antigens.

》The immune system is divided into non-specific (innate) immune system and
specific (adaptive) immune system.

Question 2

The non specific (innate) immune system?

Answer 2

●The non-specific (innate) immune system includes the barriers (skin)

》the cells (macrophages, neutrophils, monocytes, the T killers).
》the humoral components (complement, lysozyme) cytokines.

The mechanisms of the innate immune system exist from birth, they are not directed against the specific antigen, but against all foreign antigens.

Question 3

The specific (adaptive) immune system?

Answer 3

●The specific (adaptive) immune system includes humoral immunity
(the antibodies produced by the B-lymphocytes);

cell immunity (T-lymphocytes)

the cytokines.

These mechanisms are directed against the specific antigen and are activated after the contact with this antigen.

The specific immune response is induced by the so-called antigen-presenting cells
(monocytes, macrophages, dendritic cells).

They can phagocytize antigens and digest them with the generation of the peptides MHC (the major histocompatibility complex) proteins, which can be recognized by the T-lymphocytes.

》The specific immune response results
in the cell-mediated immune response leading to the activation of cells that eliminate the infected cells or cancer cells (cytotoxic T-lymphocytes and natural killers) and humoral immune response resulting in the production of antibodies against the specific antigen. (Fig. 59).

Question 4

Cytokines?

Answer 4

●Cytokines are small proteins that participate in the transduction of the
signals between cells.

they are especially important for the generation of the immune responses.

》They include a large family of interleukins as well as interferons, tumor necrosis factors.

Question 5

Pathology of the immune system?

Answer 5

》hypersensitivity reactions
》autoimmune disorders
(Reactions against self antigens)
》immunodeficiencies

Question 6

Modern classification of hypersensitivity reactions?

Answer 6

Type I ,II ,III ,IV

Question 7

Type I?

Answer 7

●An immediate hypersensitivity (anaphylactic reactions), it is mediated through the antibodies of the IgE class, which are adsorbed on the surface of the mast cells,
for example:
non-infectious bronchial asthma,
skin rash (urticaria),
anaphylactic shock.

Question 8

Type II reactions?

Answer 8

●cytotoxic reactions (antibody-dependent)
》anti-bodies of IgM or IgG classes react with the cell membrane,

》》for example:
rhesus-conflict,
reactions on the blood transfusion, thrombocytopenia,
some kinds of drug allergy

Question 9

Type III reactions?

Answer 9

immune complex reactions,
》Immune complexes of the antigens with antibodies precipitate on the vascular wall and cause inflammation,

for example:
rheumatoidematosus, glomerulonephritis;

Question 10

Type IV reactions?

Answer 10

●cell-mediated

(delayed hypersensitivity)
delayed-type allergy,

mediated by an T cells (natural killers),

for example:
rejection of transplants,
infectious bronchial asthma.

Question 11

Classificaton of drugs acting on the immune system?

Answer 11

●drugs for the treatment of the immediate-type hypersensitivity;

●immunosuppressive drugs (immunosuppressants).

●drugs for the treatment of the immunodeficiencies (immunostimulants).

Question 12

Pathogenesis of the immediate type hypersensitivity reactions (allergy)?

Answer 12

●The first exposure to an antigen lead to the transformation of the B-lymphocytes to the plasma cells that can secrete the antibodies of immunoglobulin E (IgE).

These antibodies attach to the surface of the mast cells.

In another exposure to the antigen antibodies of IgE class interact with the
antigen leading to the release of mediators of allergy

(histamine, serotonin,bradykinin, prostaglandins, leukotrienes, etc.),

which cause the symptoms
of allergy.

Question 13

Classificaton of the drugs? (Treatment of immediate hypersensitivity)

Answer 13

●histamine H1 receptor antagonists:

》1st generation drugs: diphenhydramine,
chlorpheniramine,
clemastine,
meclizine, etc.

》2nd generation drugs:
loratadine,
desloratadine,
fexofenadine,
cetirizine, etc.

●glucocorticoid hormones: prednisolone,
hydrocortisone,
betamethasone,
triamcinolone,
beclomethasone,
fluticasone, etc.

●mast cell stabilizers:

cromoglicic acid - INN (cromolyn sodium nedocromil sodium,
ketotifen

●functional antagonists of the mediators of the immediate-type hypersensitivity:

epinephrine,

broncholytics (see “Drugs acting on the respiratory system”).

Question 14

Histamine H1 receptor antagonists?

Answer 14

●Histamine H₁ receptor antagonists block the effects of the histamine
and reduce such symptoms of allergy like itching and edema.

They are used mainly in the

urticaria (allergic rash)
and
allergic rhinitis (hay fever).

》In bronchial asthma these drugs are not effective because several mediators are involved in this disease, a role of histamine is not significant.

》The first generation drugs penetrate to the CNS and cause sedation
as an adverse effect.

》The second generation histamine H₁ receptor antagonists do not penetrate to the CNS and do not cause sedation.

Question 15

Glucocorticoid hormones?

Answer 15

Glucocorticoid hormones have several mechanisms of the beneficial effect in the immediate-type allergy.

• inhibition of synthesis and release of some mediators of allergy
(prostaglandins, leukotrienes);

• inhibition of chemotaxis and function of lymphocytes, neutrophils,macrophages.

• decrease of vascular permeability;

• increase of sensitivity of adrenoceptors and increase of effects of epinephrine and other adrenergic agonists (especially important in bronchial
asthma).

Glucocorticoids are used in the following allergic disorders:
》skin allergy:
prednisolone,
hydrocortisone,
triamcinolone,
betamethasone as ointments and creams;
》bronchial asthma:
beclomethasone or fluticasone as aerosols.
in severe cases (status asthmaticus) prednisolone can be used IV.

》allergic rhinitis: beclomethasone or fluticasone as nasal sprays;

》severe allergic reactions
(anaphylactic shock, angioedema)

prednisolone is used IV
(the benefits of corticosteroids in anaphylactic shock are unproven).

Question 16

Mast cell stabilizers?

Answer 16

Mast cell stabilizers prevent the release of the mediators of allergy from
the mast cells.

They are used for the prevention of attacks of bronchial asthma (by inhalation way)
or
as nasal spray in the allergic rhinitis (cromolyn sodium).

Now, these drugs are largely displaced by inhalation glucocorticoids,

which have higher efficacy.

Ketotifen combines the properties of a
mast cell stabilizer with the histamine H₁ receptor antagonist properties.

Question 17

Functional antagonists of the mediators of the immediate-type hypersensitivity?

Answer 17

●Induce the effects opposite to the effects of histamine and other
mediators of allergy.

For example,

epinephrine in anaphylactic shock causes
the increase of the blood pressure and bronchodilation

(the mediators of allergy cause fall of the blood pressure and bronchial constriction)

Question 18

Treatment for anaphylactic shock?

Answer 18

● Anaphylactic shock is a severe kind
of an immediate-type allergic reaction, which is induced by the release of a
large amount of the histamine and other mediators of allergy.
The most important symptoms are:

》fall of the blood pressure with fainting, dizziness,
loss of consciousness
》dyspnea (impairment of breathing) due to the constriction of the
bronchial smooth muscles and edema of bronchial mucosa.

The main drug for the treatment of anaphylactic shock is epinephrine
(for adults it should must be given IM (0.5 ml 0.1% solution, repeat each 5 min)

the intravenous injection of epinephrine is not recommended due to the risk
of life-threatened cardiac arrhythmias).

The mechanism of the action of epinephrine in anaphylactic shock include.
1) the increase of the blood pressure
due to the vasoconstriction.
2) the improvement of breathing due to the relaxation of bronchial muscles and reducing mucosal edema.

Glucocorticoids
(prednisolone or hydrocortisone intravenously)
are also often administered but
their effect in these conditions was not confirmed enough.

Question 19

Immunosuppressants?

Answer 19

●Drugs inhibit immune responses.
●Used mainly in organ transplantation & autoimmune diseases

Common adverse effects
》Increased incidence of infections and malignant tumours.

Question 20

Classification (Immunosuppressants)?

Answer 20

●glucocorticoids:
prednisolone, dexamethasone, etc.

●cytotoxic drugs:
methotrexate,
azathioprine,
leflunomide,
cyclophosphamide;

●calcineurin inhibitors:
cyclosporine,
tacrolimus

● other synthetic immunosuppressants: sirolimus,
mycophenolate mofetil,
thalidomide;

●antibodies:
-polyclonal: antilymphocyte globulin (ALG),
antithymocyte globulin (ATG)

• monoclonal:
  against CD3 protein of T cells (muromonab-CD3),
  against IL-2 (basiliximab),
  against TNF (adalimumab, infliximab)

Question 21

Glucocorticoids?

Answer 21

The mechanism of the immunosuppressive action includes,

》the decrease of the production of the cytokines (interleukins, TNF) due to the inhibition of the transcriptions of their genes.

》the inhibition of the proliferation and mobilization of the lymphocytes and macrophage
(mainly the activated cells);

》the inhibition of the secretion of the antibodies.

They are used in,
organ transplantation
and
the autoimmune diseases
(rheumatoid arthritis,
systemic lupus erythematosus,
multiple sclerosis, etc.).

(For more information see “Steroidal hormones, their synthetic analogs and antagonists”.)

Question 22

Cytotoxic drugs?

Answer 22

》The general mechanism of the immunosuppressive action is the impairment of the synthesis of the nucleic acid in the proliferating cells.

The immune cells are more sensitive to cytotoxic drugs because they are rapidly proliferating.

Question 23

Methotrexate?

Answer 23

Methotrexate is an antimetabolite of the folic acid
(antimetabolites are the substances that are chemically related to some metabolites participating in the physiological processes and interfere with the utilization of these metabolites).

》Folic acid is necessary for the DNA synthesis, and
methotrexate inhibits the formation of the tetrahydrofolate - the active form
of the folic acid.

》Thus, it leads to the impairment of the DNA transcription.
》Methotrexate is used in autoimmune disorders
(rheumatoid arthritis,
psoriasis).

Question 24

Azathioprine?

Answer 24

Azathioprine is a purine antimetabolite. It is used in
organ transplantation,
rheumatoid arthritis,
systemic lupus erythematosus

Question 25

Leflunomide?

Answer 25

》Leflunomide is a pyrimidine antimetabolite
(inhibits pyrimidine synthesis).
It is used in rheumatoid arthritis.

Question 26

Cyclophosphamide?

Answer 26

●Cyclophosphamide is an alkylating drug, it causes binding the alkyl group
to the DNA leading to the impairment of the DNA synthesis.

》It is used in
rheumatoid arthritis,
systemic lupus erythematosus.

》Cytotoxic drugs cause many adverse effects because they influence
other cells,
not only the immune cells.

The most common adverse effects
are the bone marrow suppression (leucopenia,
anemia,
thrombocytopenia),

》the increased possibility of infections and tumors due to the decrease
function of the immune system.

The tumor cells are also very sensitive to the cytotoxic drugs,
so these drugs are widely used for chemotherapy of the malignant tumors (see “Anticancer drugs”).

Question 27

Calcineurin inhibitors?

Answer 27

●Calcineurin is an enzyme (phosphatase) which is necessary for the activation of the transcription of the gene responsible for interleukin-2.

》Calcineurin inhibitors
(cyclosporine, tacrolimus) form a complex with the intracellular protein cyclophillin,
and this complex inhibits calcineurin;
as a consequence,

the transcription of the gene responsible for interleukin-2 is blocked, and the differentiation of the effector
T cells responsible for the immunologic reactions is inhibited.

So, in comparison with the cytotoxic drugs calcineurin inhibitors have more selective influence on the immune cells.

Calcineurin inhibitors are used mainly for organ transplantation.

Cyclosporine was recently approved for the treatment of
rheumatoid arthritis.

The most dangerous adverse effect of the calcineurin inhibitors is
nephrotoxicity.

Also, they can cause
dysfunction of the liver,
hypertension,
hyperglycemia,
hyperkalemia.

Question 28

Other synthetic immunosuppressants.
Sirolimus (rapamycin) & its analog everolimus.

Answer 28

●are the so-called inhibitors of the molecular target of rapamycin (mTOR).

The mTOR is a key component of a complex intracellular signaling pathway involved in various physiological processes,
including the activation of
T- and B-lymphocytes by interleukin-2 and
other cytokines.

So, the blockade of mTOR leads to the inhibition of interleukin-2 dependent on the proliferation of the T cell and the B cells.

These drugs are used in organ transplantation, sirolimus also is used with
the coronary stents
(sirolimus-coated stents) for prevention of coronary restenosis.

Sirolimus can be used together with cyclosporin (synergistic effect).

Everolimus has similar effects to the effects of sirolimus but has higher bioavailability.

Adverse effects:
bone marrow suppression,
hepatotoxicity,
diarrhea.

Question 29

Mycophenolate mofetil?

Answer 29

●Inhibits
inosine monophosphate dehydrogenase,
which is important for the synthesis of the guanine nucleotides in
the T- and B-lymphocytes.

It is used in
organ transplantation,
adverse effects are gastrointestinal and blood disorders.

Question 30

Thalidomide?

Answer 30

●is an immunomodulatory drug with the complicated mechanism of influence on the immune system.
It inhibits the tumor necrosis factor alpha (TNF-alpha),

reduces phagocytosis by neutrophils,
increases the production of interleukin-10,

alters the adhesion molecule expression,
and
enhances the cell-mediated immunity via interactions with the T cells.

Application:
1) multiple myeloma
2) leprosy (erythema nodosum)
3) lupus erythematosus.

Adverse effects:
a) polyneuropathy
(impairment of peripheral nerves)
b) the formation of the blood
clots, which can lead to myocardial infarction or stroke.

Question 31

Antibodies in immunopharmacology?
Polyclonal antibodies?

Answer 31

●They are derived from the different immune cells
and
bind to different sites of an antigen. ●They are relatively inexpensive.
Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are obtained
by immunization of horses, sheep, or rabbits with the human lymphoid
cells,
they contain antibodies against the human T cells.

ALG and ATG are used in organ transplantation.

Adverse effects are relatively common,
》allergic reactions including anaphylactic shock
》 cytokine release syndrome (hypotension, high fever; pulmonary edema and death can occur)
it develops as a result of the interaction of the antibodies with the T cells which release cytokines

》increased risk of some malignant tumors especially lymphomas;
》local reactions at the site of the injection (pain, erythema).

Question 32

Monoclonal antibodies?

Answer 32

》They are produced by the immune cells which are clones of one cell, these antibodies bind to the same part of an antigen.

》They are produced by hybridoma technology.
Isolated B cells obtained from a mouse that can produce antibodies are fused with the cells of myeloma
(malignant tumor of plasma cells).

The line of the cells which is obtained is called hybridoma,
these cells are rapidly proliferating and
can produce a high amount of the antibodies.

Question 33

Muromonab-CD3?

Answer 33

●Contains the murine antibodies against the CD3 proteins
(surface proteins of the T cells).

》They are used in organ transplantation
(only to treat the rejection of the graft but not to prevent).
》Among adverse reactions, allergic reactions and cytokine release syndrome are common.

Modern technologies allow to obtain chimeric and humanized monoclonal antibodies.

In humanized monoclonal antibodies the protein sequence is modified to be maximally close to the protein sequence of human antibodies.

Chimeric monoclonal antibodies have only some fragments identical to human antibodies, other fragments are murine.

Humanized monoclonal antibodies have the endings -umab or -zumab, chimeric monoclonal antibodies have the endings -imab or -ximab.

It is necessary to stress that the preparations of the monoclonal
antibodies are very expensive.

Question 34

basiliximab?

Answer 34

》The anti-IL-2 monoclonal antibody basiliximab blocks the effects
of the interleukin-2 which is necessary for the activation of T cells.
》It is used (intravenously) in organ transplantation
(to prevent the graft rejection
in kidney transplantation).

》》》Adverse effects include

gastrointestinal disorders,
pain and redness at the site of injection, insomnia,
hypertension,
increased risk of respiratory infections.

Question 35

infliximab & adalimumab?

Answer 35

●The anti-TNF monoclonal antibodies infliximab and adalimumab block
the effects of the TNF-alpha,

which is involved in the regulation of the
functions of the immune cells and,

in general, has a significant contribution
to the inflammation.
These drugs are used in the treatment of rheumatoid arthritis
and some other inflammatory disorders.

The most common adverse effects are an increased risk of infections, allergic reactions.

Monoclonal antibodies are used not only in immunopharmacology.
Antitumor antibodies are especially useful (see “Anticancer drugs”).

Question 36

Drugs for treatment of immunodeficiencies?
(Immunostimulants)

Answer 36

●These drugs increase the immune response in patients with the impairment of some components of the immune system.

》They are used in immunodeficient states, chronic infections, and tumors.

Question 37

Classificaton? (Immunostimulants)

Answer 37

●cytokines: interferons (interferon-alpha,
interferon-beta,
interferongamma),

interleukins (interleukin-2),
tumor necrosis factor alpha.

●drugs of bacterial origin:
BCG vaccine,
ribomunil

● preparations of the thymus.
thymosin alpha-1

● drugs of synthetic origin:
levamisole

●drugs of the plant origin:
preparations of Echinacea.

Question 38

Cytokines?

Answer 38

》They are the proteins, produced by the immune cells,
cytokines are responsible for the communication between the cells in order to elaborate the immune response.

Cytokines include the interferons
(alpha,beta and gamma),

interleukins
(31 are known at this moment, from
interleukin-1 to interleukin-31),

a tumor necrosis factor and colony-stimulating factors.

Question 39

Interferons?

Answer 39

》Interferons are usually produced in response to viral infections.
》They stimulate the immune response by
1) the activation of the macrophages,
natural killers, the cytotoxic T-lymphocytes

2) the increased expression
of the so-called major histocompatibility complex, i.e. protein responsible
for the presentation of the antigens.

●The immunostimulant effect is more
significant for the interferon-gamma.

》The interferons also induce an anti-viral effect (see “Antiviral drugs”), inhibit the proliferation of the tumor
cells.

Application:
●only the interferon-gamma is used as an immunostimulant drug in the chronic granulomatous disease
(a hereditary disorder of the immune system)
as subcutaneous injections.
●interferon-alpha is used mainly as an antiviral drug in the hepatitis C and B (see Antiviral drugs) or in some tumors (chronic myelogenous leukemia,
melanoma, Kaposhi’s sarcoma).

●The interferon-beta is used in multiple
sclerosis, in this case, it acts rather as an immunosuppressive drug, decreasing number of the inflammatory cells.

The adverse effects of the interferons include….
fever,
chills,
muscle pain,
headache,
leukopenia,
anemia,
depression.

Question 40

Interleukin-2?

Answer 40

●Approved for the immune therapy of some malignant tumors.
(malignant melanoma,
metastatic renal cancer),
●it is injected subcutaneously.

The mechanism of the action of the interleukin-2 is the activation of the T-lymphocytes and natural killers.

The adverse effects can be the same as for the interferons.
》Other interleukins are investigated intensively.

Question 41

Tumor necrosis factors?
(TNF-alpha and TNF-beta)

Answer 41

●Tumor necrosis factors
(TNF-alpha and TNF-beta) inhibit the formation and proliferation of the tumor cells,
stimulate the function of the macrophages and neutrophils,

participate in the mechanisms of the inflammation.

The tumor necrosis factor alpha is sometimes used as an intraarterial injection in the treatment of tumors (melanoma, some kinds of sarcoma).

●The TNF inhibitors are now used in the treatment of inflammatory disorders, especially rheumatoid arthritis (see “Anti-inflammatory drugs”).

●The colony-stimulating factors filgrastim
(the granulocyte colony-stimulating factor)
and
sargramostim
(the granulocyte-macrophage colony-stimulating factor) are described in the chapter “Drugs acting on the blood”.

Question 42

Immunostimulants if bacterial origin?

Answer 42

●They contain weakened forms
of bacteria,
》which do not cause only specific activation of the immune response against these bacteria but also induce the non-specific activation of the immune system contributing to the elimination of other foreign cells.

Question 43

BCG vaccine?

Answer 43

●BCG vaccine is a vaccine against tuberculosis,
but it is also used as a non-specific immunostimulant in bladder cancer.

● it is given directly into the urinary bladder through a catheter.

The mechanism of the action
can involve
the activation of the macrophages and the T cells.

Question 44

Ribomunyl?

Answer 44

●Ribomunyl contains ribosomes of several bacteria
(Klebsiella pneumoniae,
Streptococcus pneumoniae, Streptococcus pyogenes,
Haemophilus influenza),

which are among the most common causes of the bacterial infections of the respiratory tract.

●It is claimed that ribomunyl induces the immune response against the above-mentioned microorganisms, so it
is used in chronic respiratory infections.

Question 45

Preparations of the thymus.
Thymosin alpha-1?

Answer 45

●Thymosin alpha-1 is a peptide producing by the thymus.

●It stimulates the differentiation of the T-lymphocytes.
●It is used subcutaneously in some tumors and infections
(including hepatitis B and C),
also in some kinds of immunodeficiencies with the
impairment of the functions of the T-lymphocytes
(especially DiGeorge syndrome).

The adverse effects are mainly due to the irritation at the site of the injection (local pain,
erythema,
edema).

Question 46

Synthetic immunostimulants?
Levamisole

Answer 46

》Levamisole has been used for a long time as the antihelmintic drug.

》But later it was found that this drug can also enhance the immune response.

●The mechanism of the immunostimulant
action of levamisole includes the activation of the T-lymphocytes and
macrophages, the increase of the secretion of the interleukins.

It is used as the immunostimulant drug in colon cancer (in clinical trials levamisole increased the survival of the patients).

●In the USA levamisole is not
used either as immunostimulant or as antihelminthic drug due to the adverse effects.

The most dangerous adverse effect, which is sometimes caused by levamisole is agranulocytosis;

● other adverse effects include,,,
dermatitis,
flu-like syndrome (fever, myalgia, fatigue).

Question 47

Immunostimulants of plant origin.
Echinacea.

Answer 47

●Echinacea
(Echinacea purpurea is the most widely used species)
is the most known plant with the immunostimulant properties.

The mechanism of the action on the immune system includes
a) the increase of the phagocytosis.
b) the increase of the number of the leukocytes.
c) the activation of the natural killers
d) the increased production of the cytokines.

The Echinacea possesses also
anti-bacterial, antiviral and anti-inflammatory activity.

The extract of Echinacea is used mainly in patients with
》respiratory tract infections (the efficacy is not sufficiently proven).

The adverse effects include
》flu-like syndrome,
》gastrointestinal disorders,
》skin rash.